Dysregulation and restoration of translational homeostasis in fragile X syndrome.

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01545, USA.

2

Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

3

Center for Neural Science, New York University, New York City, New York 10003, USA.

Abstract

Fragile X syndrome (FXS), the most-frequently inherited form of intellectual disability and the most-prevalent single-gene cause of autism, results from a lack of fragile X mental retardation protein (FMRP), an RNA-binding protein that acts, in most cases, to repress translation. Multiple pharmacological and genetic manipulations that target receptors, scaffolding proteins, kinases and translational control proteins can rescue neuronal morphology, synaptic function and behavioural phenotypes in FXS model mice, presumably by reducing excessive neuronal translation to normal levels. Such rescue strategies might also be explored in the future to identify the mRNAs that are critical for FXS pathophysiology.

Cytoplasmic polyadenylation element-binding protein (CPEB) associates with CPEs in the 3′ untranslated region (UTR) of target mRNAs and stimulates translation by promoting lengthening of the poly(A) tail. Neuroguidin is a eukaryotic initiation factor 4E (eIF4E)-binding protein (4E-BP) that binds to CPEB to prevent this CPE-dependent translation. It is known that excessive translation in fragile X syndrome (FXS) model mice is normalized by genetic reduction of CPEB, although the mechanisms through which the two proteins interact are currently unclear. In the left panel, CPEB is shown associated with fragile X mental retardation protein (FMRP) and neuroguidin, which in turn interacts with the ‘cap’-binding factor eIF4E. This configuration of factors would be hypothesized to silence mRNAs that are bound by both FMRP and CPEB. As shown in the right panel, group 1 metabotropic glutamate receptor (mGluR; not shown) activation could lead to poly(A)-tail elongation and dissociation of neuroguidin from eIF4E, thereby allowing for the assembly of the eIF4F complex (which consists of eIF4E, eIF4G and eIF4A) on the cap and the initiation of translation. In this scenario, FMRP remains bound to the mRNA and S6K1 phosphorylates the initiation factors and ribosomal protein S6 on the 40S subunit to stimulate translation. m7G, 7-methyl-guanosine.